Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling

Background/aims: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic Cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic Cancer and disclosed the underlying mechanism.

Methods: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic Cancer was measured using EdU staining, colony formation, Apoptosis, migration and invasion assays. Reactive Oxygen Species (ROS) production was measured using 2'-7'-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic Cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic Cancer.

Results: SFN can inhibit pancreatic Cancer cell growth， promote Apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic Cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic Cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic Cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group.

Conclusion: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic Cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic Cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic Cancer.